Testicular germ cell tumors are the most common affecting young adult to middled-aged men and they are the fifth most rapidly increasing type of cancer. The genetic control of susceptibility is complex and mutated genes contributing to inherited risk have not yet been identified. We are studying an animal model, the 129/Sv inbred mouse strain, in which testicular germ cell tumors (TGCTs) arise spontaneous by 3-weeks of age. Our long-range goal is to use this modelsystem to discover susceptibility genes in the mouse and then use them to evaluate inherited risk to TGCTs in humans. Specific Aim 1 involves completing the positional cloning of the Ter gene. This gene causes severe germ cell deficiency and dramatically increased risk for TGCTs. The proposed positional cloning work is based on genetic and physical map that we have completed, complementation of several aspects of the Ter phenotype in BAC transgenic mice, and cDNA and genome sequence analysis. Specific Aim 2 involves the positional cloning of a gene near Mgf and deleted in the SlJ mutation that results in increased TGCT susceptibility in mice and probably also in humans. Specific Aim 3 involves testing whether the five known TGCT genes (Ter, Trp53, Ay, and Tgct1) interact to increase or decrease TGCT susceptibility or to switch susceptibility from unilateral to bilateral cases. Specific Aim 4 involves characteristics of ENU-induced mutations that we have discovered that affect TGCT susceptibility. Together these studies will provide insight into the biology and genetics of the primordial germ cell lineage and into the etiology and pathogenesis of TGDTs.